Antimicrobial guanidinium and thiouronium functionalized polymers

Abstract

Antimicrobial cationic polycarbonates and polyurethanes have been prepared comprising one or more pendent guanidinium and/or isothiouronium groups. Additionally, antimicrobial particles were prepared having a silica core linked to surface groups comprising a guanidinium and/or isothiouronium group. The cationic polymers and cationic particles can be potent antimicrobial agents against Gram-negative microbes, Gram-positive microbes, and/or fungi.

What is claimed is: 
     
       1. A method, comprising:
 forming an initial polymer by organocatalyzed ring opening polymerization of a cyclic carbonate monomer of formula (M-6): 
 
       
         
           
           
               
               
           
         
       
       wherein
 ring atoms of (M-6) are numbered 1 to 6, 
 L b  is a divalent linking group comprising 1 or more carbons, 
 E′ is a substituent capable of undergoing a nucleophilic substitution reaction with a thiourea to form an isothiouronium group, 
 each R′ is an independent monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons, and 
 R″ is a monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons; and 
 treating the initial polymer with the thiourea, thereby forming a cationic polymer, the cationic polymer comprising a cationic subunit of formula (A-1): 
 
       
         
           
           
               
               
           
         
       
       wherein
 atoms numbered 1, 2, 3, 4, 5, and 6 of (A-1) are backbone atoms of the cationic polymer, 
 m is 1 or 2, 
 n is 0 or 1, wherein when m is 2, n is 0, 
 each R′ is an independent monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons, 
 R″ is a monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons, and 
 each Q″ is an independent group comprising a isothiouronium group. 
 
     
     
       2. The method of  claim 1 , wherein each R′ is hydrogen. 
     
     
       3. The method of  claim 1 , wherein R″ is methyl or ethyl. 
     
     
       4. The method of  claim 1 , wherein the cationic polymer is a polycarbonate. 
     
     
       5. The method of  claim 1 , wherein E′ is a halide selected from the group consisting of chloride, bromide, and iodide. 
     
     
       6. The method of  claim 1 , wherein the isothiouronium group has the structure 
       
         
           
           
               
               
           
         
       
       where each X′ is a negative-charged counterion. 
     
     
       7. The method of  claim 1 , wherein the cationic polymer is capable of killing a Gram-positive bacterium, a Gram-negative bacterium, and/or a fungus. 
     
     
       8. The method of  claim 1 , wherein the ring opening polymerization is initiated by a mono-alcohol. 
     
     
       9. The method of  claim 1 , wherein the ring opening polymerization is initiated by a diol. 
     
     
       10. The method of  claim 1 , wherein the ring opening polymerization is initiated by a particle comprising alcohol and/or amine surface groups. 
     
     
       11. The method of  claim 1 , wherein the cyclic carbonate monomer has a structure in accordance with formula (M-7): 
       
         
           
           
               
               
           
         
       
       wherein
 ring carbon 5 is labeled, 
 L c  is a divalent linking group comprising 2 to 30 carbons, 
 E′ is a substituent capable of undergoing a nucleophilic substitution reaction with a thiourea to form an isothiouronium group, and 
 R″ is a monovalent radical selected from the group consisting of hydrogen, halogens, and alkyl groups comprising 1 to 6 carbons. 
 
     
     
       12. The method of  claim 1 , wherein the initial polymer comprises an electrophilic repeat unit according to formula (M-8): 
       
         
           
           
               
               
           
         
       
       wherein
 backbone atom 5 is labeled, 
 L c  is a divalent linking group comprising 2 to 30 carbons, 
 E′ is a substituent capable of undergoing a nucleophilic substitution reaction with a thiourea to form an isothiouronium group, and 
 R″ is a monovalent radical selected from the group consisting of hydrogen, halogens, and alkyl groups comprising 1 to 6 carbons. 
 
     
     
       13. The method of  claim 1 , wherein the cyclic carbonate monomer has a structure in accordance with formula (M-9): 
       
         
           
           
               
               
           
         
       
       wherein
 ring carbon 5 is labeled, 
 L d  is a divalent linking group comprising 2 to 30 carbons, 
 E′ is a substituent capable of undergoing a nucleophilic substitution reaction with a thiourea to form an isothiouronium group, 
 each R′ is an independent monovalent radical selected from the group consisting of hydrogen, halogens, methyl, and ethyl, and 
 R″ is a monovalent radical selected from the group consisting of hydrogen, halogens, and alkyl groups comprising 1 to 6 carbons. 
 
     
     
       14. The method of  claim 1 , wherein the initial polymer comprises an electrophilic repeat unit according to formula (M-10): 
       
         
           
           
               
               
           
         
       
       wherein
 backbone carbon 5 is labeled, 
 L d  is a divalent linking group comprising 2 to 30 carbons, 
 E′ is a substituent capable of undergoing a nucleophilic substitution reaction with thiourea to form an isothiouronium group, 
 each R′ is an independent monovalent radical selected from the group consisting of hydrogen, halogens, methyl, and ethyl, and 
 R″ is a monovalent radical selected from the group consisting of hydrogen, halogens, and alkyl groups comprising 1 to 6 carbons. 
 
     
     
       15. The method of  claim 1 , wherein the cyclic carbonate monomer is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and combinations thereof. 
     
     
       16. The method of  claim 1 , wherein the cationic polymer is capable of killing a microbe on contact. 
     
     
       17. The method of  claim 16 , where the microbe is a Gram-positive microbe, Gram-negative microbe, and/or a fungus. 
     
     
       18. A method, comprising:
 conducting an organocatalyzed ring opening polymerization of a cyclic carbonate monomer using a particle comprising i) a core and ii) nucleophilic alcohol and/or amine surface groups covalently linked to the core, the surface groups capable of initiating the ring opening polymerization, thereby forming an initial polymer-modified particle, the cyclic carbonate monomer having a structure according to formula (M-6): 
 
       
         
           
           
               
               
           
         
       
       wherein
 ring atoms of (M-6) are numbered 1 to 6, 
 L b  is a divalent linking group comprising 1 or more carbons, 
 E′ is a substituent capable of undergoing a nucleophilic substitution reaction with a thiourea to form an isothiouronium group, 
 each R′ is an independent monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons, and 
 R″ is a monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons; and 
 treating the initial polymer-modified particle with the thiourea, thereby forming a second polymer-modified particle comprising a cationic polymer chain covalently linked to one of the surface groups, the cationic polymer chain comprising a cationic subunit of formula (A-1): 
 
       
         
           
           
               
               
           
         
       
       wherein
 atoms numbered 1, 2, 3, 4, 5, and 6 of (A-1) are backbone atoms of the cationic polymer, 
 m is 1 or 2, 
 n is 0 or 1, wherein when m is 2, n is 0, 
 each R′ is an independent monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons, 
 R″ is a monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons, and 
 each Q″ is an independent group comprising a isothiouronium group. 
 
     
     
       19. The method of  claim 18 , wherein the core of the particle is silica. 
     
     
       20. The method of  claim 18 , wherein the core of the particle is a silica gel. 
     
     
       21. The method of  claim 18 , wherein the surface groups comprise amine groups. 
     
     
       22. The method of  claim 18 , wherein the particle has a median size between 5 nm and 200 micrometers. 
     
     
       23. The method of  claim 18 , wherein the cationic polymer chain is capable of forming a complex by non-covalent interactions with a biologically active material selected from the group consisting of drugs and genes.